Resolving complex duplication variants in autism spectrum disorder using long-read genome sequencing
Bibliographic record
Abstract
Rare or de novo structural variation, primarily in the form of copy number variants, is detected in 5%–10% of autism spectrum disorder (ASD) families. While complex structural variants involving duplications can generally be detected using microarray or short-read genome sequencing (GS), these methods frequently fail to characterize breakpoints at nucleotide resolution, requiring additional molecular methods for validation and fine-mapping. Here, we use Oxford Nanopore Technologies PromethION long-read GS to characterize complex genomic rearrangements (CGRs) involving large duplications that segregate with ASD in five families. In total, we investigated 13 CGR carriers and were able to resolve all breakpoint junctions at nucleotide resolution. While all breakpoints were identified, the precise genomic architecture of one rearrangement remained unresolved with three different potential structures. The findings in two families include potential fusion genes formed through duplication rearrangements, involving IL1RAPL1–DMD and SUPT16H–CHD8 . In two of the families originating from the same geographical region, an identical rearrangement involving ANK2 was identified, which likely represents a founder variant. In addition, we analyze methylation status directly from the long-read data, allowing us to assess the activity of rearranged genes and regulatory regions. Investigation of methylation across the CGRs reveals aberrant methylation status in carriers across a rearrangement affecting the CREBBP locus. In aggregate, our results demonstrate the utility of nanopore sequencing to pinpoint CGRs associated with ASD in five unrelated families, and highlight the importance of a gene-centric description of disease-associated complex chromosomal rearrangements.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".